慢性HCV肝炎抗病毒疗效预测及临床.ppt

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1、NaturalHistoryofHCVinfectionExposureSelfResolution15%ChronicInfectionLiverCirrhosisEndStageLiverDiseaseLiverTransplantHepatocellularCarcinomaDeath85%Stable80%(68%)20%(17%)25%(4%)SlowlyProgressive75%(13%)20-30yrAlcoholHIVHBVImmunosuppressionOlderageBcel

2、lCD8+CTLHepatocyteCD4+ThcellYYYYYNKNKTcellsImmuneresponsetoHCVinfection:Rolelargelyunknown-early,vigorous,multi-specificresponse-strongNS3-responseinresolvingacuteHCV-TH1inrecovery-TH2inchronic-vigorous,multi-specificresponse-CTLexertsomecontrolonviral

3、loadantibodiestomoststructuralandnon-structuralviralproteinsaremadeBiologicalActivitiesofIFNSignalISGIFN-inducedproteinInhibitionofviralreplicationInhibitionofCellGrowthRegulationofCelldifferentiationActivationofImmuneSystemIFN非特异型抗病毒功能IFNReceptor2‘-5’

4、OASRNARnaseLSingle-StrandRNAs降解Mxproteinvirus多聚酶抑制PKRproteinsynthesisi抑制IFNimmunomodulatoryeffects增加MHCI激活MNKCTLcells诱导Th1cells减少Th2cells抑制IL-1、8、10和TNF→抗炎IFNProteinKinasePKRinactiveInitiationFactoreIF-2aPhosphorylatedInitiationFactoreIF-2aPPhosphatase

5、(soluble)PimRNAtranslationinhibitionProteinKinasePKRactivedsRNAssRNAReducedcapacityofmatureDCfromHCVpatientstoinduceallogeneicTcellproliferation.Bainetal.Gastroenterology120:51-524,2001AntagonismofIFNbyHCVproteinsIFNProteinKinasePKRinactiveInitiationFa

6、ctoreIF-2aPhosphorylatedInitiationFactoreIF-2aPPhosphatase(soluble)PimRNAtranslationinhibitionProteinKinasePKRactivedsRNAssRNAHCVE2HCVNS5A影响IFN抗HCV治疗的因素性别年龄种族体重感染HCV时间细胞免疫状态、肝脏纤维化程度、脂肪变程度、胰岛素抵抗HCV基因型、准种、病毒含量ISDR变异、E2胞膜蛋白与eIF-2a的同源性病毒下降的速度以前是

7、否治疗治疗药物、剂量、给药方法、联合用药PP人群197例临床特征临床特征和病毒学指标数值男/女134/63年龄≥50/<50岁49/148HCV感染途径输血/非输血130/67IFN治疗史治疗后复发/IFN初治53/144血小板记数163.3±72.87AST/ALT比值≥1/<122/175HCVRNA载量≥8×105IU/ml97<8×105IU/ml100HCV基因型基因1型154非基因1型43治疗药物Roferon-A98Pegasys99各临床特征患者和病毒学指标的ETVR和SVR临床特

8、征和病毒学指标ETVR(%)SVR(%)性别男/女54.48/57.1430.60/23.81年龄≥50/<50岁51.02/56.7620.41/31.08HCV感染途径输血/非输血53.03/60.0026.52/32.31IFN治疗史治疗后复发/IFN初治56.60/54.8633.96/26.39AST/ALT比值≥1/<154.55/55.4331.82/28.00HCVRNA载量(IU/ml)≥8×105/<8×10553.61/57.0028.87/28